Genetics of Obesity in Yup'ik Eskimos

肥胖是一种常见的可预防的发病和死亡原因，少数民族，独立于 社会经济地位，受到不成比例的影响。已知遗传和环境因素 在肥胖症的发展中很重要，然而基因内多态性变体之间的相互作用， 尽管环境风险因素具有根本重要性，但人们对其了解甚少。我们的初步数据 研究表明，中心体脂肪在爱斯基摩人中很常见，这是一个“处于危险之中”和得不到充分服务的人群， 在阿拉斯加西南部。本修订申请的目的是调查选择的基因- 环境相互作用是爱斯基摩人肥胖的危险因素。肥胖基因组连锁扫描 在多项独立研究中，涉及以下染色体区域，包括10 cM的基因组 我们在Yup'ik爱斯基摩人中进行的子扫描：2 p，3q，5 p，6p，7 q，10 q，11 q，17 p和20 q。我们搜索了 在这些区域中的生物学上合理的候选基因，并优先考虑七个基因进行详尽的遗传学研究。 调查：脂联素（3q 27）、AMP激酶γ 2亚单位和核呼吸因子-1（7 q36）， 硬脂酰辅酶A去饱和酶（10 q23），固醇调节元件结合蛋白（17 p11），胰岛素敏感性葡萄糖 转运蛋白（17 p13）和肝细胞核因子4 α（20 q12）。这些基因及其编码的蛋白质 受多不饱和脂肪酸（PUFAs）和身体活动的调节， 参与脂联素表达的因子。爱斯基摩人传统上吃富含多不饱和脂肪酸的食物， 非常活跃，但现代化导致了饮食和活动水平的巨大差异 在个体之间。 我们试图检验这一假设，即这些生物学上合理的候选基因的多态性是 对PUFA可用性和身体活动减少敏感，这些相互作用最终影响 爱斯基摩人体内脂肪堆积的程度为了达到这个目标，我们的具体目标是： 将我们现有的800多个相互关联的Yup'ik爱斯基摩人的数据集扩展到1000个家庭成员; 鉴定七个候选基因中的SNPs;检测这些基因与肥胖表型的关联; 并检测基因与环境以及基因与基因的相互作用。我们的优势包括：（1）我们的 持续访问，并与Yup'ik Eskimos建立了良好的研究伙伴关系;（2）大型定义明确的 家系;（3）PUFA摄入量和体力活动水平高度可变。 肥胖症的治疗只取得了一定的成功，也许是因为复杂的病因是 大部分未知。从这项研究中获得的基因-环境相互作用的发现将进一步促进我们的研究。 了解肥胖，并将与未来旨在开发和测试干预措施的研究相关， 并确定肥胖症的新治疗靶点。

Obesity is a common preventable cause of morbidity and mortality, and ethnic minorities, independent of socioeconomic status, are disproportionately affected. Genetic and environmental factors are known to be important in the development of obesity, yet the interactions between polymorphic variants within genes and environmental risk factors are poorly understood despite their fundamental importance. Our preliminary data demonstrate that central body fat is common among Yup'ik Eskimos, an "at risk" and underserved population in Southwest Alaska. The objective of this revised application is to investigate whether selected gene- environment interactions are risk factors for obesity in Yup'ik Eskimos. Obesity genome linkage scans have implicated the following chromosomal regions in multiple independent studies, including a 10cM genome sub-scan we conducted in Yup'ik Eskimos: 2p, 3q, 5p, 6p, 7q, 10q, 11q, 17p and 20q. We searched for biologically plausible candidate genes in these regions and prioritized seven genes for exhaustive genetic investigation: adiponectin (3q27), AMP kinase gamma 2 subunit and nuclear respiratory factor-1 (7q36), stearoyl CoA desaturase (10q23), sterol regulatory element binding protein (17p11), insulin sensitive glucose transporter (17p13), and hepatocyte nuclear factor 4 alpha (20q12). These genes and their encoded proteins are regulated by polyunsaturated fatty acids (PUFAs) and physical activity, and several code for transcription factors involved in adiponectin expression. Yup'ik Eskimos have traditionally eaten a diet rich in PUFAs, and were extremely active, but modernization has resulted in dramatic differences in diet and activity levels among individuals. We seek to test the hypothesis that polymorphisms in these biologically plausible candidate genes are sensitive to reduced PUFA availability and physical activity, and that these interactions ultimately influence the degree of body fat accumulation in Yup'ik Eskimos. To achieve this objective, our specific aims are: to extend our current data set of over 800 interrelated Yup'ik Eskimos to 1000 family members; to exhaustively identify SNPs in the seven candidate genes; to test these genes for association with obesity phenotypes; and to test for gene-environment and gene-gene interactions. Strengths of our approach include: (1) our ongoing access to, and excellent research partnership with, Yup'ik Eskimos; (2) large well-defined pedigrees; and (3) highly variable levels of PUFA intake and physical activity. Treatment for obesity has been only modestly successful, perhaps because the complex etiology is largely unknown. The discovery of gene-environment interactions gained from this study will further our understanding of obesity and will be relevant to future studies aimed at developing and testing interventions, and identifying novel therapeutic targets for obesity.